This invention is directed to methods for the dealkylation of phosphonate esters by use of trimethylchlorosilane as the dealkylating agent. In particular, this invention is directed to the discovery that high yields for the dealkylation of phosphonate esters can be achieved within relatively short reaction times by the use of trimethylchlorosilane provided that the dealkylation procedure occurs in a compatible solvent. In a preferred embodiment, the reaction is conducted in a sealed container.
This invention is further directed to novel compositions used in the methods of this invention.
The following publications are cited in this application as superscript numbers:
1 Kim, et al., Acyclic Purine Phosphonate Analogues as Antiviral Agents. Synthesis and Structure-Activity Relationships, J. Med. Chem., 33:1207-1213 (1990)
2 Schultze, et al., Practical Synthesis of the anti-HIV Drug, PMPA, Trahedron Letters, 39:1853-1856 (1998)
3 Tsai, et al., Prevention of SIV Infection in Macaques by (R)-9-(2-Phosphonylmethoxypropyl)adenine, Science, 270:1197-1199
4 Kosolopoff, et al., Organophosphorus Compounds, John Wiley and Sons, New York, N.Y. (1950)
5 McKenna, et al., Functional Selectivity in Phosphonate Ester Dealkylation with Bromotrimethylsilane, J.C.S. Chem. Comm., p. 739 (1979)
6 McKenna, et al., The Facile Dealkylation of Phosphonic Acid Dialkyl Esters by Bromotrimethylsilane, Tetrahedron Letters, 2:155-158 (1977)
7 Rabinowitz, The Reactions of Phosphonic Acid Esters with Acid Chlorides. A Very Mild Reaction, J. Org. Chem., 28:2975-2978 (1963)
8 Machida, et al., A Useful Methodfor the Dealkylation of Dialkyl Phosphonates, Synthetic Communications, 9(2):97-102 (1979)
9 Morita, et al., A Convenient Dealkylation of Dialkyl Phosphonates by Chlorotrimethylsilane in the Presence of Sodium Iodide., Tetrahedron Letters, 28:2523-2526 (1978)
10 Klug, et al., J. Org. Chem., 44:4847 (1979)
11 Hampton, et al., J. Am. Chem. Soc., 95:4404-4414
12 Holy, et al., Collect. Czech. Chem. Commun., 52:2801-2809 (1987)
13 Papapoulos, et al., Bone, 13:S41-S49 (1992)
14 Ebetino, et al., Rev. Contemp. Pharmacother., 9:233-243 (1998)
15 Bilezikian, et al., Bone Biol., 1037 (1996)
16 Nakumura, et al., Journal of Antibiotics, 48:1134 (1995)
17 Magnin, et al., J. Med. Chem., 38:2596 (1995)
18 Goto, et al., Chem. Pharm. Bull., 44:547 (1996)
19 Rowosky, et al., Biochem. Pharmacol., 35:3327 (1986)
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
Numerous antiviral agents described in the literature are phosphonate compounds. Examples of such antiviral compounds include acyclic purine phosphonates as described by Kim et al.1 and 9-[2-(phosphonomethoxy)ethyl]-adenine and R-9-[2-(phosphonomethoxy)propyl]adenine as described by Schultze, et al.2,3.
Phosphonate compounds have also been described for use in treating bone degeneration/osteoporosis13-15, in relationship to platlet activating factors, herbicical antibiotics16, in relationship to cholesterol drugs17-18, and with anti-neoplastic agents.19 Accordingly, phosphonate compounds have a wide diversity of uses in the medicinal arts.
Such phosphonates can be represented by the general formula: 
where X and Xxe2x80x2 are independently selected from hydrogen, alkyl and halogen and R is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic. Preferred antiviral phosphonate compounds are represented by the formula: 
wherein A and B are, for example, alkylene, substituted alkylene, alkylene-O-alkylene, or alkylene-S-alkylene; X is, for example, hydrogen, hydoxyl or amino; and Y is, for example, hydrogen or amino.
The synthesis of these phosphonates typically proceeds through intermediates employing phoshonate esters which are employed as blocking or protecting groups. Subsequent removal of these groups reestablishes the phosphonate functionality which typically occurs as the terminal step in the synthesis. Conventional methods for dealkylating phosphonate esters include reaction with aqueous solutions of concentrated HCl or HBr. However, many of the functional groups on the phosphonates are acid labile which cannot tolerate these harsh acidic conditions.4 
Milder reagents to effect dealkylation are trialkylsilylhalides which selectively cleave PO alkylesters yielding trialkylsilyl esters which are readily hydrolyzed with water (pHxcx9c7). Trimethylbromosilane (TMSBr) is the most commonly used reagent in this class due to its high reactivity and chemoselectivity.5,6 However, the use of trimethylbromosilane requires special handling procedures due its high corrosivity (relative to trimethyl-chlorosilane) and this compound is approximately three times more expensive than the corresponding trimethylchlorosilane. Such differences provide a compelling basis to employ trimethylchlorosilane as the reagent of choice in the dealkylation of phosphonate esters.
Notwithstanding the above, the use of trimethylchlorosilane as a dealkylation reagent in reactions with phosphonate esters has been hindered by its poor reactivity (relative to trimethylbromosilane). In this regard, the literature is replete with references stating that prolonged reaction times and/or poor yields arise from use of trimethylchlorosilane in such dealkylation reactions.6-9 
In order to address this problem, it has been reported that the addition of either sodium or lithium iodide to the reaction medium results in substantially faster reaction times and provided high yields of the product.8,9 However, the addition of such salts was also reported to lead to contamination of the resulting phosphonate product with lithium halide salts requiring crystallization of this product as its monoanilinium salt to effect removal of this salt.8 
In view of the above, methods to efficiently effect dealkylation of phosphonate esters in high yield with trimethylchlorosilane would be particularly desirable. Preferably, such methods would not employ alkali iodide salts such that purification of the resulting products would be simplified.
This invention is based on the novel and unexpected discovery that dealkylation of phosphonate esters using trimethylchlorosilane can be consistently achieved for a wide variety of ester groups in the absence of added alkali iodide salts by use of a solvent. In experiments reported below, the combination of trimethylchlorosilane and solvent provided for almost quantitative recovery of dealkylated product in approximately 10% of the time required by prior art processes employing no solvent. Subsequent hydrolysis of the trialkylsilyl phosphonate provided for desired phosphonate in almost quantitative amounts.
In view of the above, this invention is directed to methods for dealkylation of phosphonate esters using trimethylchlorosilane as the dealkylating agent. Specifically, in a first method aspect, this invention is directed to a method for dealkylation of phosphonate esters which method comprises:
(a) combining a phosphonate ester and trimethylchlorosilane in a solvent in the absence of alkali iodide salts; and
(b) maintaining the resulting reaction mixture under conditions wherein the phosphonate ester is converted to trimethylsilyl phosphonate.
In one preferred embodiment, the reaction is conducted in a sealed reaction vessel.
In another preferred embodiment, the trimethylsilyl phosphonate is subsequently hydrolyzed in an aqueous solution under conditions which provide for the phosphonic acid [i.e., R1 and R2 (if present) are hydrogen].
In still another preferred embodiment, the methods of this invention are employed to dealkylate bisphosphonate esters (i.e., compounds of formula I wherein both R1 and R2 are other than hydrogen).
In another of its method aspects, this invention is directed to a method for dealkylation of phosphonate esters which method comprises:
(a) adding a phosphonate ester to a solvent within a sealable container;
(b) adding trimethylchlorosilane to the sealable container defined in (a) above;
(c) sealing the container;
(d) maintaining the sealed container under conditions wherein the phosphonate ester is converted to silyl phosphonate; and
(e) hydrolyzing the silyl phosphonate to provide for the dealkylated phosphonic acid or a salt thereof.
Preferably, the phosphonate ester is represented by a compound of either formula I or II: 
wherein R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and R3 is an organic moiety linked to the phosphorous atom by a carbon atom. Typically, R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkylene-O-alkyl, substituted alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-substituted alkyl, alkylene-S-alkyl, substituted alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-substituted alkyl, alkylene-O-alkyenyl, alkylene-O-substituted alkyenyl, aryl, heteroaryl and heterocyclic and salts thereof and with the proviso that, in formula I, at least one of R1 and R2 is other than hydrogen and in formula II, R1 is not hydrogen.
Preferred R3 groups include, by way of example only, alkylene-O-alkylene-B, alkylene-O-substituted alkylene-B, alkylene-O-alkenylene-B and alkylene-O-substituted alkenylene-B which are exemplified by the groups which include xe2x80x94CH2OCH(CH3)CH2B, xe2x80x94CH2OCH(CH2OH)CH2B, xe2x80x94CH2OCH(CH2N3)CH2B, xe2x80x94CH2OCH(CH2F)CH2B,xe2x80x94CH2OCH(Cxe2x89xa1CH)CH2B and xe2x80x94CH2OCH(CHxe2x95x90CH2)CH2B where B is a base such as adenine, guanine, guanosine, cytosine, thymine, inosine, uridine, thiouridine, and substituted variants thereof wherein such bases are substituted with 1-4 substituents selected from substituents recited for substituted heteroaryl groups.
Particularly preferred phosphonate esters for use in this invention are represented by the formula: 
wherein R1 and R2 are as defined above, A and B are selected from the group consisting of alkylene, substituted alkylene, alkylene-O-alkylene, alkylene-O-substituted alkylene, substituted alkylene-O-alkylene, substituted alkylene-O-substituted alkylene, alkylene-S-alkylene, substituted alkylene-S-alkylene, alkylene-S-substituted alkylene, substituted alkylene-S-substituted alkylene, alkylene-O-alkenylene, alkylene-O-substituted alkenylene, substituted alkylene-O-alkenylene, substituted alkylene-O-substituted alkenylene, alkylene-S-alkenylene, substituted alkylene-S-alkenylene, alkylene-S-substituted alkenylene, and substituted alkylene-S-substituted alkenylene; X is selected from the group consisting of hydrogen, hydoxyl and amino; and Y is selected from the group consisting of hydrogen and amino.; X is selected from the group consisting of hydrogen, hydoxyl and amino; and Y is selected from the group consisting of hydrogen and amino.
Even more preferred phosphonate esters are represented by formulas III and IV below: 
wherein R1, R2, X and Y are as defined above; Z is selected from the group consisting of alkylene, substituted alkylene and alkylene-O-alkylene; and n is an integer of from 1 to 10.
Specific phosphonate esters include those defined in Tables I and II below:
In still another of its method aspects, this invention is directed to a method for dealkylation of bisphosphonate esters which method comprises:
(a) adding a bisphosphonate ester to a solvent within a sealable container wherein the bisphosphonate ester is represented by formulas below: 
xe2x80x83wherein each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic, and X, Y, Z and n are as defined above;
(b) adding trimethylchlorosilane to the sealable container defined in (a) above;
(c) sealing the container;
(d) maintaining the sealed container under conditions wherein the bisphosphonate ester is converted to bis(silyl) phosphonate of the formula: 
xe2x80x83wherein X, Y, Z and n are as defined above; and
xe2x80x83(e) hydrolyzing the bis(silyl) phosphonate to provide for the phosphonates of the formula: 
wherein X, Y, Z and n are as defined above; and salts thereof.
Preferably, the salts of such compounds are pharmaceutically acceptable salts.
In one preferred embodiment, the solvent is selected from the group consisting of chlorobenzene, dimethylformamide, acetonitrile, dichloroethane, n-butylchloride, 2-butylchloride, n-pentylchloride, 2-chloropentane, 1-chlorooctane, trichloroethane, chloroform, cyclopentylchloride, chlorocyclohexane, chlorobenzene, 2-chlorotoluene, o-dichlorobenzene, 1-chloronaphthlene, 4-chlorobenzotrichloride, 2-chlorobenzotrifluoride, 3-chlorobenzotrifluoride, 4-chlorobenzotrifluoride, chlorodibromomethane, chlorodibromofluoromethane, benzene, toluene, o-xylene, propionitrile, valeronitrile, benzonitrile, dimethylacetamide, dimethylpropionamide, 1-methylpyrrolidin-2-one, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butryate, methyl caproate, ethyl caproate, butyl acetate, ethyl isovalerate, methyl ethyl ketone, ethyl propyl ketone, methyl iso-butyl ketone, 3-methyl-2-butanone, methyl iso-amyl ketone, and the like.
In one preferred embodiment, the solvent is selected to have a dielectric constant of greater than about 5. In another preferred embodiment, the solvent is selected to have a polarity index of greater than about 2.5. Even more preferably, the solvent is selected to have a boiling point of greater than about 60xc2x0 C.
In another preferred embodiment, the reaction is conducted in the absence of added iodide salts such as lithium iodide and sodium iodide. xe2x80x9cAbsencexe2x80x9d of iodide salts means that insufficient iodide salt is present to detectably change the rate of dealkylation by greater that 10%, preferably 0%, at any point in the reaction.
In one of its composition aspects, this invention is directed to a composition comprising a phosphonate ester, trimethylchlorosilane and a solvent with the proviso that said composition does not include any alkali iodide salts.
As noted above, this invention is directed to methods for the dealkylation of phosphonate esters by use of trimethylchlorosilane as the dealkylating agent. However, prior to defining this invention in further detail, the following terms will first be defined. Any terms not defined herein have their art recognized meanings.
Definitions The term xe2x80x9csolventxe2x80x9d refers to aprotic solvents, i.e. aprotic polar or nonpolar solvents. xe2x80x9cSolventxe2x80x9d includes those solvents which solubilize at least one phosphonate ester, preferably at least at a level of 30 mg/mL. The solvent is preferably selected from the group consisting of chlorobenzene, dimethyl-formamide, acetonitrile, dichloroethane, n-butylchloride, 2-butylchloride, n-pentylchloride, 2-chloropentane, 1-chlorooctane, trichloroethane, chloroform, cyclopentyl-chloride, chlorocyclohexane, chlorobenzene, 2-chlorotoluene, o-dichlorobenzene, 1-chloronaphthlene, 4-chlorobenzotrichloride, 2-chlorobenzotrifluoride, 3-chlorobenzotrifluoride, 4-chlorobenzotrifluoride, chlorodibromomethane, chlorodibromofluoromethane, benzene, toluene, o-xylene, propionitrile, valeronitrile, benzonitrile, dimethylacetamide, dimethylpropionamide, 1-methylpyrrolidin2-one, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butryate, methyl caproate, ethyl caproate, butyl acetate, ethyl isovalerate, methyl ethyl ketone, ethyl propyl ketone, methyl iso-butyl ketone, 3-methyl-2-butanone, methyl iso-amyl ketone, and the like. Suitable solvents can be readily determined merely by assessing their utility in the methods of this invention as exemplified in the examples below. Particularly preferred solvents include, for example, chlorobenzene, dimethylformamide, acetonitrile and dichloroethane.
Preferably, the solvent is selected to have a dielectric constant of greater than about 5 or a polarity index of greater than about 2.5.
More preferably, the solvent is selected to have a boiling point of greater than about 60xc2x0 C.
The term xe2x80x9csealable containerxe2x80x9d refers to containers which exhibit a leakage of less than 5 psi per hour with an initial pressure of 50 psi. Preferably, the sealable container exhibits a leakage of less than 2 psi per hour with an initial pressure of 50 psi. More preferably, the sealable container exhibits a leakage of less than 1 psi per hour with an initial pressure of 50 psi.
The term xe2x80x9calkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl and n-decyl and the like.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. This term is exemplified by groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the like.
The term xe2x80x9calkylenexe2x80x9d refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH213 ), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (i.e., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94) and the like.
The term xe2x80x9csubstituted alkylenexe2x80x9d refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures.
The term xe2x80x9calkoxyxe2x80x9d refers to the groups alkyl-Oxe2x80x94, alkenyl-Oxe2x80x94, cycloalkyl-Oxe2x80x94, cycloalkenyl-Oxe2x80x94, and alkynyl-Oxe2x80x94, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferred alkoxy groups are alkyl-Oxe2x80x94 and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
The term xe2x80x9csubstituted alkoxyxe2x80x9d refers to the groups substituted alkyl-Oxe2x80x94, substituted alkenyl-Oxe2x80x94, substituted cycloalkyl-Oxe2x80x94, substituted cycloalkenyl-Oxe2x80x94, and substituted alkynyl-Oxe2x80x94 where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
The term xe2x80x9calkenylxe2x80x9d refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), iso-propenyl (xe2x80x94C(CH3)xe2x95x90CH2), and the like.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9calkenylenexe2x80x9d refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-3 sites of vinyl unsaturation. This term is exemplified by groups such as ethenylene (xe2x80x94CHxe2x95x90CHxe2x80x94), the propenylene isomers (e.g., xe2x80x94CH2CHxe2x95x90CHxe2x80x94 and xe2x80x94C(CH3)xe2x95x90CHxe2x80x94) and the like and includes all positional isomers such as cis and trans isomers.
The term xe2x80x9csubstituted alkenylenexe2x80x9d refers to an alkenylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures.
The term xe2x80x9calkynylxe2x80x9d refers to a monoradical of an unsaturated hydrocarbon preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH) and the like.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, and xe2x80x94SO2-heteroaryl.
The term xe2x80x9cacylxe2x80x9d refers to the groups HC(O)xe2x80x94, alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, cycloalkenyl-C(O)xe2x80x94, substituted cycloalkenylC(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94 and heterocyclicxe2x80x94C(O)xe2x80x94 where alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9cacylaminoxe2x80x9d or xe2x80x9caminocarbonylxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9csulfonylaminoxe2x80x9d refers to the group xe2x80x94NRSO2Ra where R is hydrogen, alkyl, substituted alkyl, aralkyl, or heteroaralkyl, and Ra is alkyl, substituted alkyl, amino, or substituted amino wherein alkyl, substituted alkyl, aralkyl, heteroaralkyl and substituted amino are as defined herein.
The term xe2x80x9caminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, amino, substituted amino, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9caminoacyloxyxe2x80x9d or xe2x80x9calkoxycarbonylaminoxe2x80x9d refers to the group xe2x80x94NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9cacyloxyxe2x80x9d refers to the groups alkyl-C(O)Oxe2x80x94, substituted alkyl-C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, substituted cycloalkyl-C(O)Oxe2x80x94, aryl-C(O)Oxe2x80x94, heteroaryl-C(O)Oxe2x80x94, and heterocyclic-C(O)Oxe2x80x94 wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term xe2x80x9carylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). The aryl group may optionally be fused to a heterocyclic or cycloalkyl group. Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, sulfonylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
The term xe2x80x9caryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to the group xe2x80x94NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that both R""s are not hydrogen.
The term xe2x80x9ccarboxyalkylxe2x80x9d or xe2x80x9calkoxycarbonylxe2x80x9d refers to the groups xe2x80x9cxe2x80x94C(O)O-alkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted alkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-cycloalkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted cycloalkylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-alkenylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-substituted alkenylxe2x80x9d, xe2x80x9cxe2x80x94C(O)O-alkynylxe2x80x9d and xe2x80x9cxe2x80x94C(O)O-substituted alkynylxe2x80x9d where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein.
The term xe2x80x9ccycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, said cycloalkyl group may optionally be fused to an aryl or heteroaryl group. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
The term xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9ccycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
The term xe2x80x9csubstituted cycloalkenylxe2x80x9d refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). The heteroaryl ring may optionally be fused to a cycloalkyl or heterocyclyl ring. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, xe2x80x94SO-alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl and trihalomethyl. Preferred heteroaryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
The term xe2x80x9cheteroaryloxyxe2x80x9d refers to the group heteroaryl-Oxe2x80x94.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclylxe2x80x9d refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring and further wherein one, two, or three of the ring carbon atoms may optionally be replaced with a carbonyl group (i.e., a keto group). Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, xe2x80x94SOxe2x80x94alkyl, xe2x80x94SO-substituted alkyl, xe2x80x94SO-aryl, xe2x80x94SO-heteroaryl, xe2x80x94SO2-alkyl, xe2x80x94SO2-substituted alkyl, xe2x80x94SO2-aryl and xe2x80x94SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.
Examples of heteroaryls and heterocycles include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, morpholine, tetrahydrofuranyl, tetrahydrothiophene, and the like as well as N-alkoxy-nitrogen containing heterocycles.
The term xe2x80x9cheterocyclooxyxe2x80x9d refers to the group heterocyclic-Oxe2x80x94.
The term xe2x80x9cthioheterocyclooxyxe2x80x9d refers to the group heterocyclic-Sxe2x80x94.
The term xe2x80x9coxyacylaminoxe2x80x9d or xe2x80x9caminocarbonyloxyxe2x80x9d refers to the group xe2x80x94OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term xe2x80x9cthiolxe2x80x9d refers to the group xe2x80x94SH.
The term xe2x80x9cthioalkoxyxe2x80x9d or xe2x80x9calkylthioxe2x80x9d refers to the group xe2x80x94S-alkyl.
The term xe2x80x9csubstituted thioalkoxyxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
The term xe2x80x9cthioaryloxyxe2x80x9d refers to the group aryl-Sxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
The term xe2x80x9cthioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
As to any of the above groups which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
Methodology
The methods of this invention may be conducted by the following methods and procedures. It should be appreciated that where typical or preferred process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Specifically, dealkylation and hydrolysis of phosphonate esters involve a two-step procedure as shown in reaction (1) below. Reaction (1) depicts for illustrative purposes only dealkylation and hydrolysis of bisphosphonate esters and, it is understood, of course, that other phosphonates can be similarly dealkylated (e.g., R1 being an ester and R2 being hydrogen). In any event, reaction (1) is illustrated as follows: 
wherein R1, R2 and R3 are as defined above and TMSCl refers to trimethyl-chlorosilane.
In reaction (1), phosphonate ester 1 is combined with a solvent preferably in a sealable container such as, for example, a glass pressure reactor preferably containing a thermowell and a pressure gauge. The reaction can also be conducted on an industrial scale using a Pfaulder reactor as a sealable container. The particular sealable container employed is not critical and the selection of a suitable sealable containers is well within the skill of the art.
The amount of solvent employed in this reaction preferably ranges from about 50 to about 90 weight percent of the total weight of the solvent plus phosphonate ester 1 and more preferably from about 60 to about 80 weight percent.
Preferably, at least a stoichiometric equivalent of trimethylchlorosilane 2 per each ester present on phosphonate ester 1 is added to the sealable container in order to effect dealkylation of the ester functionalities on the phosphonate ester. In one preferred embodiment, trimethylchlorosilane 2 is employed at from about 1.5 to about 2 equivalents relative to each ester present on phosphonate ester 1. It is understood, of course, that an excess of trimethylchlorosilane 2 will speed reaction completion and, accordingly, an excess of this reagent is often employed in sluggish reactions.
After all of the reagents have been added, the container is preferably sealed and then maintained under conditions to effect dealkylation of the phosphonate ester to provide for the (silyl) phosphonate 3. Preferably, the reaction proceeds under an inert atmosphere (e.g., nitrogen or argon) by heating the container to a temperature of from about 90xc2x0 C. to about 140xc2x0 C. Heating is continued until the reaction is complete which typically occurs within about 2 to 60 hours.
After reaction completion, hydrolysis of silyl phosphonate 3 to phosphonic acid 4 is readily achieved by the addition of water to the reaction mixture. In one embodiment, the solvent is first removed from the silyl phosphonate 3 by evaporation and then water is added to the residue to effect hydrolysis. Preferably, however, water is added directly to the reaction mixture and vigorous stirring is employed to effect hydrolysis in situ. The reaction proceeds rapidly and the resulting phosphonic acid 4 is recovered by conventional means such as chromatography, filtration, distillation, etc.
If desirable, phosphonic acid 4 can be converted to a salt thereof such as a pharmaceutically acceptable salt by conventional methods well known in the art.
The methods of this invention employ novel compositions. Accordingly, this invention is also directed to such novel compositions which comprise a phosphonate ester, trimethylchlorosilane and a solvent with the proviso that said composition does not include any alkali iodide salts.
Utility
The methods of this invention are useful in dealkylation of phosphonate esters. Such esters are well known intermediates in the synthesis of a variety of medicaments including anti-viral agents, anti-neoplastic agents, and herbicical antibiotics, medicaments used in treating bone degeneration/osteoporosis, and medicaments used in relationship to platlet activating factors and cholesterol drugs. Accordingly, the methods of this invention are useful in the synthesis of such medicinal agents.